Cancer is a disease influenced primarily by external factors. Up to 80% of human cancers arise from exposure to environmental agents. The majority of cancer is believed to be preventable because exposure to these external factors should be manageable (Giovannucci, 1999; Perera, 2000).
Human tumours result from a series of mutational events, leading to the loss of the regulatory mechanisms that govern normal cell behaviour and ultimately resulting in the formation of a tumour with full metastatic (or invasive) potential (Smith, 1995). All higher organisms have developed a complex variety of mechanisms to protect themselves from environmental insult, for example from ingested plant toxins. One of the most important protection measures involves the metabolism of toxins (or xenobiotics) leading to detoxification and ultimately excretion of the toxin (Smith, 1995). Unfortunately, the metabolic pathways do not always lead to detoxification of the toxin. Indeed many chemical carcinogens are activated by these same metabolic pathways to react with cellular macromolecules.
Improvements in genetic analysis and the availability of human genetic sequence information arising from the Human Genome Project has added another facet to the analysis of cancer susceptibility, that of inter-individual variation at the genome level. Molecular epidemiology has already begun to clarify some of the gene-environment interactions that may lead to disease. The ultimate goal of molecular epidemiology is to develop risk assessment models for individuals, and already the field has provided insight into inter-individual variation in human cancer risk (Shields, 2000). Molecular epidemiology focuses on three major determinants of human cancer risk: inherited host susceptibility factors, molecular dosimetry of carcinogen exposure, and biomarkers of early effects of carcinogenic exposure. The variability in metabolic activity, detoxification and DNA repair of the US population could be as high as 85–500-fold with correspondingly high variability in cancer risk (Hattis, 1986). Considering the latency of cancer, the importance of correlating individual risk with biomarkers at an early stage becomes apparent. These biomarkers can help to identify populations or individuals at risk of cancer resulting from specific environment-gene interactions.
Defining the factors that contribute to inter-individual variations in cancer susceptibility has been a major focus of research for many years. Given the suggested role of environmental factors in carcinogenesis, some of the candidate genes are those that encode the xenobiotic-metabolising enzymes that activate or inactivate carcinogens. Variable levels of expression of these enzymes could result in increased or decreased carcinogen activation. Other genetic factors that could contribute to cancer susceptibility include genes involved in DNA repair, proto-oncogenes, tumour suppressor genes, cell-cycle genes, as well as genes involved in aspects of nutrition, hormonal status, and immunological responses. Emerging data from the Human Genome Project has led to studies that show combinations of metabolic polymorphisms are increasingly being linked to a greater risk of cancer (Perera, 1997). Studies which have measured the formation of DNA adducts as a marker of enzyme activity have found that the levels of DNA damage or protein adducts vary considerably between persons with apparently similar exposure (Bryant, 1987; Perera, 1992; Mooney, 1995). The observed variability reflects a combination of true biologic factors, unaccounted for by differences in exposure or laboratory variation (Dickey, 1997). In fact, lower exposures to carcinogens can result in proportionately higher adduct levels because of a person's genetic predisposition for increased carcinogen metabolic activation (Kato, 1995; Vineis, 1997).
The existence of multiple alleles at loci that encode xenobiotic-metabolising enzymes can result in differential susceptibilities of individuals to the carcinogenic effects of various chemicals. Metabolism in humans occurs in two distinct phases: Phase I Metabolism involves the addition of an oxygen atom or a nitrogen atom to lipophilic (fat soluble) compounds such as steroids, fatty acids, xenobiotics (from external sources like diet, smoke, etc.) so that they can be conjugated to glutathione or N-acetylated by the Phase II enzymes (thus made water-soluble) and excreted from the body. There are superfamilies of xenobiotic-metabolising enzymes: cytochrome P450's (Phase I), GSTs (Phase II) and NATs (Phase I and II) which are thought to have evolved as an adaptive response to environmental insult. Alterations in the activity of these enzymes are predicted to result in an altered susceptibility to cancer (Hirvonen, 1999).
Enzymatic activation of xenobiotics is not, however, the only route to cancer development. Epidemiological studies suggest that nutritional factors may also play a causative role in more than 30% of human cancers. However, defining the precise roles of specific dietary factors in the development of cancer is difficult due to the multitude of variables involved (Perera, 2000). Specific dietary factors are not easily measured as a single quantifiable variable, such as number of cigarettes smoked per day. Further complications arise due to differences in methodology, control populations, types of carcinogens, and amounts of exposure to carcinogens.
Priorities for studies relating to the interrelationship of dietary factors and cancer susceptibility include identification of genetic factors that contribute to individual cancer risk, identification of cancer-preventative chemicals in fruits and vegetables, better understanding of carcinogenic role of polycyclic aromatic hydrocarbons and heterocyclic amines generated by cooking meats at high temperature, and better understanding of the role of increased caloric intake with increased cancer risk (Perera, 2000).
Increased consumption of vegetables and fruits is correlated with a decreased risk of cancer, and studies of this aspect of nutritional effects on cancer has led to the identification of other enzymes and micronutrients involved in the maintenance of a normal cellular phenotype (Giovannuci, 1999).
One quarter of the US population with low intake of fruits and vegetables has roughly twice the cancer rate for most types of cancer (lung, larynx, oral cavity, oesophagus, stomach, colon and rectum, bladder, pancreas, cervix, and ovary) when compared with the quarter with the highest intake (Ames, 1999). Fruit and vegetables are high in folate and antioxidants. Low intake can lead to micronutrient deficiency, which has been shown to cause DNA damage in a way that mimics radiation damage by causing single and double-stranded breaks, oxidative lesions or both. The micronutrients correlated with DNA-damaging activity include folate (or folic acid), iron, zinc, and vitamins B12, B6, C and E (Ames, 1999).
Of the cancers that are correlated with nutritional effects, colon cancer (colorectal neoplasia) has among the strongest links to diet. In the US, colon cancer is the fourth most common incident cancer and second most common cause of cancer death in the US, with 130,000 new cases and 55,000 deaths per year (Potter, 1999). According to the WHO, colorectal cancers are the second most common cause of cancer death in Britain (WHO, 1997). Worldwide colon cancer represents 8.5% of new cancer cases reported, with the highest rates seen in the developed world and the lowest rates in India. Colon cancer occurs with approximately equal frequency in men and women, and the occurrence appears to be highly sensitive to changes in the environment. Immigrant populations assume the incidence rates of the host country very rapidly, often within the generation of the initial immigrant (Potter, 1999).
Risk factors for colon cancer include a positive family history, meat consumption, smoking and alcohol consumption (Giovannuci, 1999). There is an inverse relationship, i.e. lower risk, associated with consumption of vegetables, high folate intakes, use of non-steroidal anti-inflammatory drugs, hormone replacement therapy and physical activity. Meat and tobacco smoke are sources of carcinogens, while vegetables are a source of folate, antioxidants, and have Phase II (detoxifying) enzyme-inducing ability (Taningher, 1999).
Diets rich in raw vegetables, green vegetables, and cruciferous vegetables have a decreased risk of colon cancer. Diets high in fibre, from vegetables and cereals, have been associated with a greater than two-fold decrease in risk of colorectal adenomas in men. The data on fruit in the diet is not as consistent to date (WCRF, 1997), but a recent report (Eberhart, 2000) measured potent anti-oxidant activity of phytochemicals in apple skins with the ability to inhibit growth of tumour cell lines in vitro, so it is possible that more clearly defined links will emerge in the future. Lower risk of colon cancer is associated with high folate intakes, but actual consumption of vegetables, rather than specific micronutrient preparations or vitamin supplements, has the most consistent low risk (Potter, 1999).
Other cancers that have been correlated with nutrition include prostate and breast. These malignancies are largely influenced by a combination of factors related to diet and nutrition. Prostate cancer is associated with high consumption of milk, dairy products and meats. These products decrease levels of 1,25(OH)2 vitamin D, which is a cell differentiator. Low levels of 1,25(OH)2 vitamin D may enhance prostate carcinogenesis by preventing cells from undergoing terminal differentiation and continuing to proliferate (Giovannucci, 1999). Breast, colon, and prostate cancers are relatively rare in less economically developed countries, where malignancies of the upper gastrointestinal tract are quite common. The cancers of the upper gastrointestinal tract have been related to various food practices or preservation methods other than refrigeration. For example, cancer of the mouth and pharynx is the sixth most common cancer world-wide and has been linked to alcohol consumption, tobacco, salt-preserved meat and fish, smoked foods and charcoal-grilled meat, as well as ingestion of beverages drunk very hot. Thus, diet can be a direct supply of genotoxic compounds or may cause chronic irritation or inflammation (Giovannucci, 1999).
In recent years, many genes involved in the processes described above and other areas of metabolism have been found to exist in allelic form. Therefore, certain populations, subpopulations, races etc have greater or lesser susceptibility to particular diseases linked with variation in alleles of some genes. For many decades, health advice, for example relating to diet, exercise, smoking, sunbathing has been issued by Governments, charities and health advisory bodies, such advice has been directed only at the population as a whole, or, at best, to groups such as the elderly, children and pregnant women. Such advice can therefore only be very general and cannot, by its very nature, take account of the particular genotype of an individual. Moreover, in recent years, there has been much media publicity of research findings on links between particular foods, drugs etc and medical conditions, often causing health scares. As the factors that contribute to disease susceptibility, for example cancer, or cardiovascular disease susceptibility vary between populations and between individuals of populations, it is often impossible for an individual to derive useful advice appropriate to his or her particular circumstances from such reports.